HISTORY OF PRESENT ILLNESS
An 18-month-old girl presented with a 1-day history of fever to 38.0°C and cough. While in the examination room, she had tonic flexion of her upper extremities and her “eyes rolled back.” This episode lasted 10 minutes and resolved spontaneously. Mild perioral cyanosis developed just before the end of the seizure. Afterward, the child was tired and irritable. There was no history of rash, eye pain, neck pain, or emesis. There were no alterations in gait or balance. There was no antecedent witnessed trauma. The only pet was a recently acquired goldfish. Several children at her daycare had symptoms of upper respiratory infection. The remainder of the review of systems was unremarkable.
The girl was born at term after an uncomplicated pregnancy. She had not previously required hospitalization. Her immunizations were up-to-date and included the pneumococcal conjugate vaccine. The child received supplemental iron starting at 12 months of age for treatment of “anemia.” The maternal grandmother had type 2 diabetes treated with glyburide, a sulfonylurea oral hypoglycemic agent. There was no family history of febrile seizures but one relative supposedly had a seizure and drowned while swimming. The family was not able to provide further details.
T 39.1°C; HR 132 bpm; RR 26/min; BP 97/53 mmHg; SpO2 98% in room air
Weight 25th percentile
The child was crying and seemed mildly disoriented. There were no bruises or abrasions on her face or scalp. Her tympanic membranes were mildly erythematous but mobile. There was copious purulent nasal discharge. The neck was difficult to assess due to the child’s lack of cooperation. While yelling and screaming, she was able to arch her back and neck without apparent limitation. There was no cervical lymphadenopathy. The heart and lung sounds were normal. The abdomen was soft without organomegaly. There were no focal neurologic deficits but the child appeared groggy and irritable and was slow to respond to her mother’s voice. Several hyperpigmented macules were noted on her skin as her clothes were removed for the lumbar puncture (Figure 11-1).
FIGURE 11-1. Photo of patient’s skin findings.
Complete blood count revealed the following: 15 500 WBCs/mm3 (61% segmented neutrophils, 22% lymphocytes, 15% monocytes, and 2% eosinophils); hemoglobin, 12.1 g/dL; and 282 000 platelets/mm3. Serum electrolytes, calcium, and glucose were normal. Urinalysis revealed no white blood cells or nitrites. Lumbar puncture revealed 2 WBCs/mm3 and 19 RBCs/mm3. No bacteria were visualized on Gram stain. The CSF protein and glucose were normal. Blood and CSF cultures were subsequently negative.
COURSE OF ILLNESS
The skin findings (Figure 11-1) suggested a diagnosis that was subsequently confirmed with further evaluation.
DISCUSSION CASE 11-1
This child presented with fever and seizures. Given the age and difficult examination, a lumbar puncture was performed to exclude meningitis as a cause of seizures. The reassuring CSF findings led to other diagnostic considerations. The maternal grandmother used an oral hypoglycemic agent making an ingestion-induced hypoglycemic seizure possible. However, the child’s serum glucose was normal. The history of a relative drowning during a reported seizure raised the specter of cardiac conditions, such as prolonged QT syndrome, Wolf-Parkinson White syndrome, and hyper-trophic cardiomyopathy, as possible causes of hypoxic seizures. The EKG, performed in light of this history, was normal.
In an 18-month-old girl presenting with a brief (<10 minute) seizure in the context of fever, simple febrile seizure is the most likely diagnosis. However, it is possible that the fever lowered the seizure threshold in a child with an underlying seizure disorder. Potentially important clues in this case were the hyperpigmented macules on the child’s skin. Café-au-lait spots, while characteristic for neurofibromatosis type 1, may also be noted in unaffected children and in other disorders. The critical factor in this case is the number of spots seen; fewer than 0.1% of normal individuals have more than six café-au-lait spots. Inherited disorders associated with café-au-lait spots are summarized in Table 11-2.
TABLE 11-2. Inherited multisystem diseases associated with café-au-lait spots.
Examination of the skin revealed approximately 15 hyperpigmented macules substantially greater than 5 mm in diameter (Figure 11-1). Axillary freckling was also noted on physical examination. An ophthalmology examination revealed findings suspicious for an optic glioma. These findings confirmed the diagnosis of neurofibromatosis type 1 (NF1). Given her age, it is likely that this child had a febrile seizure; however, the possibility of NF1 was considered by the treating physicians on the basis of the child’s skin findings. This child did not have structural brain lesions to suggest a specific cause of seizures attributable to NF.
EPIDEMIOLOGY AND INCIDENCE
NF1 and NF2 are genetic disorders in which affected patients develop both benign and malignant tumors at increased frequency. NF1 is associated with cutaneous lesions, vision loss, and skeletal problems, while cataract formation and hearing loss are more typically associated with NF2. NF1, also known as von Recklinghausen NF or peripheral NF, is an autosomal dominant condition. One-half of cases occur in patients with a family history of NF1 and the other half occur as spontaneous mutations. The incidence is approximately 1 in 3000. The clinical manifestations of NF1 result from alterations of the NF1 gene located on chromosome 17. The gene product, termed neurofibromin, is thought to function as a negative growth regulator.
Despite advances in our understanding of the molecular basis for NF1, the diagnosis remains one largely based on clinical criteria. Clinical diagnosis of NF1 requires the presence of at least two of the seven National Institutes of Health consensus criteria (Table 11-3). Children with sporadic rather than inherited cases may not meet the NIH diagnostic criteria until later in life. At 1 year of age, approximately 50% of sporadic cases lack two or more of the cardinal clinical features permitting diagnosis but by age 8 years 95% meet NIH criteria.
TABLE 11-3. Diagnostic criteria for neurofibromatosis type 1.
1) Six or more café-au-lait spots
–Greater than 1.5 cm in postpubertal children
–Greater than 0.5 cm in prepubertal children
2) Greater than 2 neurofibromas or any type of greater than1 plexiform neurofibroma
3) Freckling in the axillary or inguinal regions (Crowe sign)
4) Optic glioma
5) Two or more Lisch nodules
–Benign iris hamartomas
6) Distinctive bony lesions
–Dysplasia of sphenoid bone or long bone cortex
7) First-degree relative with neurofibromatosis type 1
–Includes parent, sibling, or offspring
*Diagnostic for neurofibromatosis type 1 if two or more criteria present
The most visible features of NF1 are flat, evenly pigmented macules known as café-au-lait spots. These macules, often present at birth, increase in both number and size over the first few years of life. One or two café-au-lait macules are present in up to 25% of the normal population but the presence of six or more macules should raise suspicion for NF1. These macules are easier to visualize using a Wood lamp. Skinfold freckling, another pigmentary change associated with NF1, usually occurs in the axillae, inguinal region, nape of the neck, or above the eyelids. By 6 years of age, approximately 80% of children with NF1 demonstrate axillary or inguinal freckling.
Lisch nodules are benign pigmented hamartomas of the iris occurring in patients with NF1. These nodules do not interfere with vision. Lisch nodules may not be apparent in young children but are present in more than 95% of adolescent and adult patients. Detection of Lisch nodules on bedside examination is challenging and diagnosis frequently requires a slit-lamp examination by an experienced ophthalmologist. In contrast to Lisch nodules, optic nerve tumors, such as optic nerve gliomas, primarily occur in younger children. They are often associated with asymmetric noncorrectable visual loss, diminished peripheral vision and color discrimination, and proptosis.
Subcutaneous or cutaneous (dermal) neurofibromas are rarely seen in young children but appear during or just before adolescence. Neurofibromas are present in 48% of 10-year-old patients and 84% of 20-year-old patients. Cutaneous lesions frequently begin as small papules on the face, scalp, trunk, and extremities. Deep lesions may be detected only through palpation. These lesions represent a major cosmetic problem but do not transform into malignant tumors. In contrast, plexiform neurofibromas surround soft tissue and bone causing aberrant growth. Plexiform neurofibromas, present in 30% of patients, are locally invasive and may transform into malignant peripheral nerve sheath tumors. They may be accompanied by overlying hyperpigmentation or hypertrichosis. Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging is proving to be useful to differentiate benign plexi-form neurofibromas from MPNSTs. Other tumors that occur with higher frequency in patients with NF1 include pheochromocytomas, juvenile chronic myeloid leukemia, and rhabdomyosarcomas.
Seizures occur in approximately 5% of patients with NF1. Seizures may be generalized or partial. In a study by Korf et al., 22 of 359 NF1 patients developed seizures. The seizures were most often characterized as complex-partial (9 patients), febrile (6 patients), or generalized epilepsy (3 patients).
Cardiovascular manifestations include hypertension, congenital heart disease, and vasculopathy. The arterial system is most affected by vasculopathy and renal artery stenosis is the most common manifestation. Other manifestations of NF1 include learning disabilities, behavioral abnormalities, pain, scoliosis, tibial dysplasia, headaches, stroke, and bowel or bladder complications (secondary to pelvic plexiform neurofibromas).
NF1 is diagnosed by the presence of clinical features mentioned previously. Evaluation should focus on symptoms associated with NF1, such as neurocognitive deficits, visual complaints, progressive neurologic deficits, altered bowel or bladder function, weakness, seizures, and headaches. Other medical complications associated with NF1 include hypertension, short stature, and precocious puberty. Once the diagnosis is made, the following management strategies should be considered.
Orthopedic referral. Tibial dysplasia appears at birth with anterolateral bowing of the lower leg. The presence of tibial bowing should prompt referral to an orthopedic surgeon familiar with the management of orthopedic problems in children with NF1. Patients should also be referred if scoliosis is noted.
Ophthalmologic referral. Symptomatic optic gliomas are diagnosed in the first year of life in 1% of NF1 patients though they typically develop between 4 and 6 years of age. They are ultimately present in 15% of patients with NF1 and cause symptoms in 2%-5% of cases. An annual vision evaluation by an experienced ophthalmologist is part of the routine follow-up for children with NF1.
Head MRI. Routine presymptomatic screening for CNS tumors is not necessary. However, any evidence of optic nerve dysfunction, seizures, or neurologic abnormalities warrants neuroimaging with special attention to the orbits.
Other radiology studies. Plain radiographs may detect a variety of bony abnormalities. They should be ordered when clinical findings suggest bony erosion secondary to an adjacent plexiform neurofibroma, scoliosis, or bone pain.
Genetic evaluation. Families who have a child with NF1 may benefit from genetic counseling. Genetic testing can be difficult due to the large number of possible mutations. Linkage analysis is offered but is not helpful in sporadically affected individuals. The use of complementary techniques permits detection of approximately 95% of mutations in those who fulfill diagnostic criteria.
Other studies. Children with NF1 should be monitored for blood pressure elevations associated with renal artery stenosis or pheochromocytomas. Approximately 6% of NF1 patients develop hypertension and a secondary cause (e.g., renal artery stenosis) is identified in one-third of cases. Learning disabilities are seen in 40%-60% of children with NF1. Children should undergo evaluation for cognitive and motor function with prompt referral or intervention as required. Plexiform neuro-fibromas grow in early childhood, are difficult to remove, and tend to regrow. A multidisciplinary team that includes the primary pediatrician as well as surgeons, radiologists, and oncologists should manage these neurofibromas.
No specific therapy is currently available. In the future, targeted therapies for NF1-associated tumors may be designed to inhibit growth-promoting pathways activated in the absence of neurofibromin. Other potential therapies focus on blockade of angiogenic factors that could potentially decrease tumor growth.
Routine office visits should focus on detection and management of complications as discussed earlier. Annual ophthalmologic examinations are important to detect optic nerve lesions. Interval history should focus on subtle sensory or motor symptoms, such as paresthesia or muscle atrophy. Pediatricians should also inquire about incontinence given the risk of spinal cord neurofibromas. Consultation with specific surgical specialists is warranted based on the location of neurofibromas. Laser treatment has not yet been proven to be successful in permanently removing café-au-lait spots.
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